Project Summary Only rare humans are naturally resistant to retroviral infections. Although genome wide association studies can identify genetic loci associated with the resistance, finding particular resistance genes within gene- rich loci has proven to be a great challenge. On the other hand, inbred mice offer a great alternative for mapping mammalian genes responsible for resistance and susceptibility to retroviruses. We have described a recessive locus named ?virus infectivity controller 1? (vic1), which is responsible for production of retrovirus- neutralizing antibodies (Ab) in mice from the I/LnJ strain (2). vic1 mediates a neutralizing Ab response against two different murine retroviruses (6, 2, 8). Thus, vic1 represents a mechanism of broad resistance against retroviruses. Using positional cloning and computational approaches we identified H2-Ob (Ob) as the gene coding for Vic1 (1). Ob encodes the beta subunit which together with alpha subunit, encoded by Oa, forms evolutionally conserved the non-classical Major Histocompatibility Complex class II-like molecule H2-O (HLA- DO in humans), a negative regulator of antigen presentation. The precise function of H2-O/HLA-DO is still debated, but it appears to be related to its ability to modify the MHC-II peptide repertoire by inhibiting another MHC-II-like molecule, H-2M (HLA-DM in humans) (9). The role of non-functional Ob in retroviral resistance was confirmed by moving the I/LnJ allele of Ob to several virus-susceptible backgrounds, such as C3H/HeN, B6, and BALB/cJ, and by producing a knock-out allele of the gene in B6 mice. All these animals produced retrovirus-neutralizing Abs. However, the effect only had high penetrance if these animals were infected as adults. In contrast, I/LnJ mice produced retrovirus- neutralizing Abs irrespective of their age at infection, even when they were infected as newborns. The finding prompted us to search for the genetic basis of resistance of I/LnJ neonates. The trait was successfully linked to a single dominant 4.1 Mb region of Chromosome 15, virus infectivity controller 2 (vic2). Vic2 function was only apparent in the absence of functional Ob. The inheritance of both non-functional Ob and vic2i conferred the ability to produce anti-virus Abs to neonatal mice from all susceptible strains. Many viruses, including retroviruses, infect adults, but are also passed from mothers to newborns during birth and breastfeeding. It is commonly accepted that the immune system of a newborn is underdeveloped, increasing the risk of infection and impairing responses to many vaccines. However, I/LnJ mice generate a virus-neutralizing immune response independent of the age at which they were exposed to the pathogen. Thus, it is fundamentally important to unravel the mechanism of Vic2?s function in order to understand the unknown features of the neonate immune system and to acquire the ability of stimulating productive pathogen-specific immunity in neonates. Identification of vic2 and the delineation of the pathway that it controls are the goals of this proposal.